1. Field of the Invention
The present invention relates to a gas chromatographic method of analysis for impurities found in sevoflurane (fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether), which is used as a pharmaceutical, as an agricultural chemical, or as an intermediate in the preparation of pharmaceuticals or agricultural chemicals and to a monitoring of impurities by a gas chromatograph in the production process of sevoflurane and a process control thereon. More specifically, the invention relates to a process for determining the adequate removal of impurities from a crude sevoflurane so that a pharmaceutically acceptable product is ultimately obtained. The impurities may be residual starting materials, byproducts of the process, or contaminants. The invention also relates to a method for the removal of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) from sevoflurane via an extraction process.
2. Description of Related Art
There have been several synthetic approaches to sevoflurane reported in the literature. For instance, sevoflurane can be obtained in accordance with a production method described in U.S. Pat. No. 3,689,571, which discloses the reaction of HFIP and a formaldehyde equivalent in the presence of an excess of anhydrous HF (hydrogen fluoride) to produce sevoflurane. This type of process is known to generate several other fluorinated ethers that must be removed from the crude sevoflurane, along with any unreacted starting materials, in order to obtain a pharmaceutically acceptable product. These impurities may be removed through a variety of methods known to those skilled in the art, including distillation, extraction, water washing, and acid/base washing, and the like. Efficient use of these methods, without causing further decomposition or side product formation, requires the accurate, quantitative isolation and identification of the impurities. This analytical process must be able to separate clearly the impurities in a reproducible fashion. Furthermore, the analytical process must be rapid enough to allow for the adjustment of the purification operation in a timely fashion.
U.S. Pat. No. 5,679,576 discloses the method of controlling a purification process by analyzing the impurities in a crude sevoflurane with gas chromatography, using a cross-linked cyanopropylmethylphenylsilicone capillary column, wherein the purification process is continued until the content of a designated impurity reaches a specified level. The method is applicable to a variety of purification processes.
In order to be most efficient and economical, it is preferable to use the fewest possible number of chromatographic columns for the analysis of all of the impurities that may be present in the sevoflurane. This principle holds true for the analysis of the finished product, particularly if the material is to be used in a pharmaceutical application. Thus, the preferred chromatographic column must be capable of clearly separating a variety of impurities including both low-boiling and high-boiling compounds, over a wide range of concentrations.
U.S. Pat. Nos. 5,391,579, 5,492,111 and 5,789,450, all describe gas chromatography of a sevoflurane product on a CARBOWAX™ (polyethylene glycol) column, but none of these patents make use of the column to analyze multiple impurities in the sevoflurane product. U.S. Pat. No. 5,969,193 also describes gas chromatography of a sevoflurane product on a CARBOWAX™ (polyethylene glycol) column, but the column is not a capillary column, and does not permit the resolution of very small amounts of various impurities in the sevoflurane product.